The blue in these mosquitoes shows where genes for resisting malaria parasites will be active.

The blue in these mosquitoes shows where genes for resisting malaria parasites will be active.

A.A. James

Gene drive turns insects into malaria fighters

The war against malaria has a new ally: a controversial technology for spreading genes throughout a population of animals. Researchers report today that they have harnessed a so-called gene drive to efficiently endow mosquitoes with genes that should make them immune to the malaria parasite—and unable to spread it. On its own, gene drive won’t get rid of malaria, but if successfully applied in the wild the method could help wipe out the disease, at least in some corners of the world.

The approach “can bring us to zero [cases],” says Nora Besansky, a geneticist at the University of Notre Dame in South Bend, Indiana, who specializes in malaria-carrying mosquitoes. “The mosquitos do their own work [and] reach places we can’t afford to go or get to.”

But testing that promise in the field may have to wait until a wider debate over gene drives is resolved. The essence of this long-discussed strategy for spreading a genetic trait, such as disease resistance, is to bias inheritance so that more than the expected half of a subsequent generation inherits it. The gene drive concept attracted new attention earlier this year, when geneticists studying fruit flies adapted a gene editing technology called CRISPR-Cas9 to help spread a mutation—and were startled to find it worked so well that the mutation reached almost all fly progeny. Their report, published this spring in Sciencecame out less than a year after an eLife paper discussed the feasibility of a CRISPR-Cas9 gene drive system but warned that it could disrupt ecosystems and wipe out populations of entire species.

A firestorm quickly erupted over the risks of experimenting with gene drives, nevermind applying them in the field. The U.S. National Academy of Sciences (NAS) has convened a committee to weigh the risks and propose safeguards, and the authors of the eLife and Science papers have laid out guidelines for experiments.

Meanwhile, for the past 20 years, Anthony James, a geneticist at the University of California (UC), Irvine, dreamt of engineering a gene drive that would spread DNA that makes mosquitoes unable to host the malaria parasite. In 2012, his team pinned down mouse genes for antibodies that make rodents immune to the human malaria pathogen and put them in a mosquito species that spreads malaria in India. The antibodies, as hoped, interrupted the parasite’s life cycle within the insect. But James had no way to push those antibody genes into countless millions of mosquitoes in nature. He explored crafting a gene drive method using transposable elements, odd bits of DNA that can jump among chromosomes, but never succeeded.

Earlier this year, however, James got an email from Ethan Bier, the geneticist at UC San Diego whose lab was doing the soon-to-be-published gene drive research in fruit flies. Bier thought he had a solution to James’s dilemma. “As soon as we saw [gene drive] could work, we thought of mosquitoes,” Bier says. James was thrilled. "I looked at their data and realized [they] made what I proposed obsolete.”

But he wondered whether Bier’s gene drive system could ferry the hefty 17,000 bases of DNA containing the mouse antibody genes. “The question was, ‘Would it carry a large cargo that would remain active?’” James recalls. He and Bier teamed up to see.

Valentino Gantz from Bier’s lab and Nijole Jasinskiene, a molecular biologist at UC Irvine, began by engineering male and female Anopheles stephensi to carry the gene drive system. They had designed the system so that, along with spreading the antibody genes from one half of a chromosome pair to the other—the key to biasing inheritance—it would also cut out a piece of a gene responsible for eye color. When they mated the altered mosquitoes with normal ones, they could quickly see whether the gene drive had worked: Offspring that had inherited the antibody genes also had white eyes.

The technology was efficient, endowing about 99% of the transgenic male’s offspring with the added genes, Bier and James’s teams report today in the Proceedings of the National Academy of Sciences. And, as hoped, those genes were active in the mosquitoes. Earlier experiments had shown that if the antibody genes were expressed, they thwarted the parasite. And modeling suggests that with a gene drive of this efficiency, it should only take about 10 generations of mosquitoes for the antimalaria genes to completely infiltrate a population.

The system wasn't perfect. The gene drive didn't work as well when started in female transgenic mosquitoes. Also, the protein Cas9 used in the gene editing technology can be toxic to mosquitoes, so the team had to tweak where in the insects it was made, and how much, to improve the survival rates of the offspring. Still, the strategy clearly works. “It’s a really big deal,” Besanksy says. "It’s not just a gene drive system. It’s a gene drive system that carries the antiparasite genes.” “We’ve got all the pieces,” James adds. “It’s a question of [making] a product that people will want.”

And that is the big if. James, Bier, and their colleagues adequately addressed concerns about accidental releases of the transgenic mosquitoes, say several outside researchers contacted by Science. The insectaries were behind five sets of doors, and they used a mosquito that doesn’t survive in California, should it manage to escape.

But before such work continues, says evolutionary engineer Kevin Esvelt from Harvard University, biologists should look at the ecological effects of gene-driven changes, make sure the changes are stable over many generations, and develop a way to counter or get rid of the gene drive if problems arise.

Because the antiparasite genes should continue to spread ad infinitum among a mosquito population, national and international regulations need to be worked out before gene drives are deployed in the field, adds social scientist Kenneth Oye from the Massachusetts Institute of Technology in Cambridge. The NAS gene drive report, due out next year, may help in that regard. “How are we going to decide as a society whether, when, and how to use gene drive to solve a problem?” Oye asks.

Esvelt, who is already having discussions with the public, doctors, and government officials about spreading anti–Lyme disease genes in mice even though gene drives haven’t been demonstrated in mammals, says some consensus must be reached. “At the end of the day, unless you have widespread public support, you can’t do it.”

James accepts that his dream may be deferred for now. “If it turns out we are too far ahead of the curve, we’ll just have to wait for people to catch up,” he says. “I hope I don’t have to wait the rest of my productive career, but if we can’t find a way to do it ethically, then it won’t be done.”

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